1. Field
Presented in this application are herbal compositions and methods that provide a treatment for prostate gland and kidney disorders. In particular, a composition for the treatment or improvement of prostatitis and methods and compositions for the treatment or improvement of prostate carcinoma and relieving symptoms and improving objective signs of prostate disorders. In a further aspect, compositions and methods related to the overall health of the kidney, including the use of an herbal combination in the reduction of polyuria, incontinence, and proteinuria, as well as relieving the symptoms of these conditions. In a still further aspect, compositions and methods that improve sexual satisfaction.
2. Description of Related Art
The kidney is either one or a pair of organs in the dorsal region of the vertebrate abdominal cavity, functioning to maintain proper water and electrolyte balance, regulate acid-base concentration, and filter the blood of metabolic wastes, which are excreted as urine. Thus, the consequence of a kidney disorder can constitute an overall imbalance in the organism as a whole. Many organs such as the bladder, intestine, heart, lungs, prostate depend on the ability of the kidney to filter out the undesirable debris of the body and maintain overall homeostasis.
In Western medicine the kidneys are known to serve several vital functions, including the removal of waste from the body in the form of urine and the filtering of toxins from the blood. The kidneys also release three important hormones: (1) Erythropoietin, or EPO, which stimulates the bone marrow to make red blood cells; (2) renin, which regulates blood pressure; and (3) the active form of vitamin D, which helps maintain calcium for bones and for normal chemical balance in the body.
Kidneys are essentially blood-cleansing organs. The renal artery from the heart brings blood into the kidneys to be cleaned by a network of millions of glomerulus containing nephrons. The nephrons filter out toxins, excess nutrients and body fluid. The remaining cleaned and filtered blood then passes through the renal veins back into circulation. The filtered out material travels down a tubule that adjusts the level of salts, water and wastes that are excreted in the urine. The renal pelvis collects the urine. From the pelvis, urine travels down the ureter to the urinary bladder. The urine is expelled from the bladder and out of the body through the urethra.
Types of kidney disease include diabetes, high blood pressure, glomerulonephritis and cysts. Diabetes effects the body's ability to regulate glucose. Excess glucose in the blood can damage the nephrons in the kidneys reducing the blood vessels' ability to filter toxins. High blood pressure can also damage the nephrons. Glomerulonephritis generally relates to a class of other diseases not related to kidney infection.
If both kidneys stop functioning due to disease, patients experience end-stage renal disease (ESRD), or total kidney failure. Kidney failure means that the body can no longer rid itself of certain toxins and cannot properly regulate blood pressure and critical nutrients. Unless those experiencing kidney failure are treated, they can die within days due to the build-up of toxins and fluid in their blood.
The prostate gland (or prostate) is a walnut-sized, mucous-producing organ in males that lies just below the urinary bladder. The prostate typically grows and enlarges throughout life. The only known function of the prostate is to produce a secretion that nourishes and protects the sperm during reproduction. The urethra passes through the prostate gland. Hypertrophy or hyperplasia of the prostate may affect the function of the urethra, usually by occlusion of the urethra.
Prostate cancer (CaP) is the most frequently diagnosed malignancy in American males and the second leading cause of cancer death in men. Greenle et al, R. T., Hill-Harmon, M. B., Murray, T. and Thun, M. Cancer statistics. CA Cancer J. Clin. 51, 15-36, 2001. The most challenging aspect in the clinical management of prostate cancer is appearance of the hormone refractory state (HRPC) for which no curable therapy is currently available. Therefore, many prostate cancer patients seek alternative forms of treatment, including dietary and herbal supplements. A shortcoming in this personalized rather than physician guided disease management is a lack of sufficient scientific data on safety, functionality, and mechanisms of action of individual herbs and complex herbal formulations. HRPC often emerges as the eventual outcome of androgen deprivation therapy used to treat the androgen dependent (AD) form of prostate cancer. Aquilina, J. W., Lipsky et al., J. J. and Bostwick, D. G. Androgen deprivation as a strategy for prostate cancer prevention. J. Natl. Canc. Inst. 89, 689-696, 1997. Timing, modulating factors, and underlying mechanisms of AD→HRPC transition are poorly understood.
The American Cancer Society predicts that there will be about 180,000 new prostate cancer cases this year, which are estimated to contribute to 32,000 deaths. Greenlee,et al R. T., Hill-Harmon, M. B., Murray, T. and Thun, M. Cancer statistics. CA Cancer J. Clin. 51, 15-36, 2001. Such statistics currently rank CaP second only to lung cancer as the leading cause of cancer death in U.S. men. Over time, however, CaP may actually exceed lung cancer as a cause of morbidity and mortality, due to an increase in adult male life expectancy and more common use of PSA screening for CaP in its early stages. Risks for CaP include unmodifiable factors such as age, race, and genetics, and modifiable factors such as diet and nutrition, occupational exposures, and possibly hormonal status. Schulman, C. C., Zlotta, A. R., Denis, L., Schroder, F. H. and Sakr, W. A. Prevention of prostate cancer. Scand. J. rol. Nephrol. Suppl. 205, 50-61, 2000.
Features of hormone-refractory prostate cancer (HRPC). Compared to other hormone-related cancers, CaP responds readily to androgen deprivation. Sixty to eighty percent of patients with localized CaP have favorable responses to surgical and medical castration, largely due to induction of apoptosis of the androgen-dependent cells. Aquilina, J. W., Lipsky, J. J. and Bostwick, D. G. Androgen deprivation as a strategy for prostate cancer prevention. J. Natl. Canc. Inst. 89, 689-696, 1997. Androgen ablation, however, often leads to the expansion of androgen-independent and -hypersensitive clones. Also, even with castration, significant amounts of steroid precursors can be synthesized in the adrenal glands and are actively converted to dihydrotestosterone (DHT) by prostatic tissues. Accordingly, androgen ablation and combined androgen blockade therapies produce marginal clinical benefits for individuals with metastatic and HRPC. In these patients, the disease ultimately progresses to an androgen-independent (AI) state for which the median survival time is about 18 months and no curative therapy is currently available. Crawford, E. D. Challenges in the management of prostate cancer. Br. J. Urol. 70 (Suppl. 1), 33-38, 1992. This dismal clinical outcome may be attributed to a number of factors. First, even at the metastatic site, only a low percentage (<5%) of CaP cells proliferate, thus making them relatively resistant to apoptosis-restoration therapies. Lin, X., Denmeade, S. R. and Isaacs, J. T. The genetics of programmed (apoptotic) cell death. Cancer Surv. 25, 173-194, 1995; Isaacs, J. T., Furuya, Y. and Berfes, R. The role of androgen in the regulation of programmed cell death/apoptosis in normal and malignant prostatic tissue. Semin. Cancer Biol. 5, 391-400, 1994. Second, HRPC cells can proliferate in an androgen-independent manner, i.e., robust growth can occur regardless of whether normal levels of androgens are present, or if androgens are drastically diminished or even completely depleted. Sader, M. D., Hussain, M. and Bruchovsky, N. Prostate cancer: molecular biology of early progression to androgen independence. Endocrine-Related cancer. 6, 487-502, 1999; Fenton, M. A., Shuster, T. D., Fertig, A. M., Taplin, M. E., Kolvenbag, G., Bubley, G. J. and Balk, S. P. Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin. Canc. Res. 3, 1383-1388, 1997; Culig, Z., Hobisch, A., Hittmair, A., Peterziel, H., Cato, A. C., Bartsch, G. and Klocker, H. Expression, structure, and function of androgen receptor in advanced prostatic carcinoma. The Prostate. 35, 63-70, 1998. Androgen-independent proliferation of HRPC cells may relate to changes in the AR, as germline or somatic mutations and/or gene amplifications, and also to the interplay of AR with growth factors and cytokines. Cells harboring AR mutations have been reported to display altered ligand specificity, which could paradoxically switch therapeutic anti-androgens from their expected inhibitory role to potent stimulators of prostate cancer cell proliferation. Kyprianou, N., Bains, A. K and Jacobs, S. C. Induction of apoptosis in androgen-independent human prostate cancer cells undergoing thymineless death. The Prostate. 25, 66-75, 1994; Akakura, K., Akimoto, S., Ohki, T. and Shimazaki, J. Antiandrogen withdrawal syndrome in prostate cancer after treatment with steroidal antiandrogen chlormadinone acetate. Urology. 45, 700-705, 1995]. Clonally expanded cells in HRPC may also harbor amplified and over-expressed wild-type AR gene. Schoenberg, M. P., Hakimi, J. M., Wang, S., Bova, G. S., Epstein, J. I., Fischbeck, K. H., Isaacs, W. B., Walsh, P. C. and Barrack, E. R. Microsatellite mutation (CAG24->18) in the androgen receptor gene in human prostate cancer. Biochem. Biophys. Res. Commun. 198, 74-80, 1994. Amplification and increased mutations of the AR, such as, expansion of CAG repeats in exon 1, changes in the ligand-binding domain and in regions flanking the AF-2 binding site, have all been reported, and shown to be present in a large percentage of HRPC specimens. Visakorpi, T., Hyytinen, E., Koivisto, P., Tanner, M., Keinanen, R., Palmberg, C., Palotie, A., Tammela, T., Isola, J and Kallioniemi, O. P. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genetics. 9, 401-406, 1995; Fenton, M. A., Shuster, T. D., Fertig, A. M., Taplin, M. E., Kolvenbag, G., Bubley, G. J and Balk, S. P. Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin. Canc. Res. 3, 1383-1388, 1997; Culig, Z., Hobisch, A., Hittmair, A., Peterziel, H., Cato, A. C., Bartsch, G. and Klocker, H. Expression, structure, and function of androgen receptor in advanced prostatic carcinoma. The Prostate. 35, 63-70, 1998; Jenster, G. The role of the androgen receptor in the development and progression of prostate cancer. Semin. Oncol. 26, 406-421, 1999; Tilley, W. D., Clarke, C. L., Birrell, S. N. and Bruchovsky, N. Hormones and cancer: new insights, new challenges. Trends Endocrinol. Metab. 12, 186-188, 2001; Tilley, W. D., Buchanan, G., Hickey, T. E. and Bentel, J. M. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin. Cancer Res. 2, 277-285, 1996. HRPC cells also show a characteristic increase in the predominance of neuroendocrine cells, interspersed among rapidly proliferating Al prostate cancer cells. Tilley, W. D., Clarke, C. L., Birrell, S. N. and Bruchovsky, N. Hormones and cancer: new insights, new challenges. Trends Endocrinol. Metab. 12, 186-188, 2001. Another feature of HRPC is the development of multi-antiapoptotic mechanisms, which also contribute to unabated cell growth. Tilley, W. D., Clarke, C. L., Birrell, S. N. and Bruchovsky, N. Hormones and cancer: new insights, new challenges. Trends Endocrinol. Metab. 12, 186-188, 2001; Tilley, W. D., Buchanan, G., Hickey, T. E. and Bentel, J. M. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin. Cancer Res. 2, 277-285, 1996. Collectively these changes are thought to culminate in an increased sensitivity of HRPC to low concentration of androgens and growth stimulation by nonclassical ligands. Since decades are required for CaP to progress to the incurable HRPC state, this form of CaP should be readily amenable to intervention. Clinically, however, because HRPC is considered heterogeneous and complex, it is less likely to respond to single agent approaches; instead, combination and/or sequential treatment strategies may be considered more promising alternatives.
Common therapies for prostate cancer include prostastectomy, radiation, cryotherapy, and/or chemotherapy. Aquilina, J. W., Lipsky, J. J. and Bostwick, D. G. Androgen deprivation as a strategy for prostate cancer prevention. J. Natl. Canc. Inst. 89, 689-696, 1997; Morris, M. J. and Scher, H. I. Novel strategies and therapeutics for the treatment of prostate carcinoma. Cancer. 89, 1329-1348, 2000. For patients with metastatic diseases, androgen deprivation via chemical or surgical means remains the last treatment modality. Sader, M. D., Hussain, M. and Bruchovsky, N. Prostate cancer: molecular biology of early progression to androgen independence. Endocrine-Related cancer. 6, 487-502, 1999; Craft, N., Shostak, Y., Carey, M. and Sawyers, C. L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nature Medicine. 5, 280-285, 1999; Craft, N. and Sawyers, C. L. Mechanistic concepts in androgen-dependence of prostate cancer. Cancer Metastasis Rev. 17, 421-427, 1999; Morris, M. J. and Scher, H. I. Novel strategies and therapeutics for the treatment of prostate carcinoma. Cancer. 89, 1329-1348, 2000. With passing time, however, cancer often becomes refractory to hormone ablation, leaving patients with metastatic disease no other conventional treatment options. Leewansangtong, S. and Crawford, E. D. Maximal androgen withdrawal for prostate cancer therapy: current status and future potential. Endocrine-Related cancer. 5, 325-339, 1998. These patients often seek unconventional “alternative” and/or “complementary” treatments, most commonly herbal therapies (phytotherapies). Such use is dramatically rising in recent years both in the U.S. and in Europe. Eisenberg, D. M., Kessler, R. C., Foster, C., Norlock, F. E., Calkins, D. R. and Delbanco, T. L. Unconventional medicine in the United States. Prevalence, costs and patterns of use. N. Engl. J. Med. 328, 246-232, 1993; Angell, M. and Kassirer, J. P. Alternative medicine-the risks of untested and unregulated remedies. N. Engl. J. Med. 339, 839-841, 1998; Risberg, T., Lund, E., Wist, E., Kaasa, S. and Wilsgaard, T. Cancer patients use of nonproven therapy: a 5-year follow-up study. J. Clin. Oncol. 16, 6-12, 1998; Eisenberg, D. M., Davis, R. B., Ettner, S. L., Appel, S., Wilkey, S., Van Rompay, M. and Kessler, R. C. Trends in alternative medicine use in the United States 1990-1997: results of a follow-up national survey. J.A.M.A. 280, 1569-1575, 1998; Pelletier, K. R., Marie, A., Krasner, M. and Haskell, W. L. Current trends in the integration and reimbursment of complementary and alternative medicine by managed care, insurance carriers and hospital providers. Am. J. Health Promot. 12, 112-122, 1997; Moyad, M. A. Alternative therapies for advanced prostate cancer. Urol. Clin. North Am. 26, 413-417, 1999. The number of patients undergoing treatment with alternative medicine in the U.S. increased from 34% in 1990 to 42% in 1997. This number is still rising and there are now more visits to alternative health practitioners than total visits to all primary care physicians. Pelletier, K. R., Marie, A., Krasner, M. and Haskell, W. L. Current trends in the integration and reimbursment of complementary and alternative medicine by managed care, insurance carriers and hospitalproviders. Am. J. Health Promot. 12, 112-122, 1997; Moyad, M. A. Alternative therapies for advanced prostate cancer. Urol. Clin. North Am. 26, 413-417, 1999; Garnick, M. B. Prostate cancer: screening, diagnosis, and management. Ann. Intern. Med. 118, 804-818, 1993.
Localized CaP is often treated by radical applications such as prostectomy, radiation therapy, and hormonal therapy such as androgen deprivation using physical or chemical castration. Initially, in the majority of patients receiving such forms of therapy there is a response, but frequently this response is followed by establishment and expansion of hormone-insensitive and refractory clones. The establishment of such states is often rapidly followed by the recurrence of disease, and metastasis to sites beyond the confines of the gland. Emergence of metastatic prostate cancer, even if detected early, is not readily treatable. Thus, what are urgently needed are new easily compliant preventative and treatment measures. Further, research directed towards mechanistic understanding of newly developed treatment modalities is also imperative.
Significant geographic variations and marked differences among various ethnic/racial groups with respect to the age-adjusted incidence and mortality rates for clinical CaP have been observed in epidemiological studies; both environmental and genetic factors and their interplays are hypothesized to contribute to the observed variable incidence. In particular, the possible involvement of diet capable of exerting promoting or protecting influences on the progression and establishment of clinically important prostate cancer have been proposed. An alternative explanation for the observed varied incidence of clinical CaP is that culture specificity and diversity, exemplified by food and other lifestyle preferences, maintain potentially metastatic CaP in a latent state.
The multi-factorial, multi-stage nature of carcinogenesis underscores the heterogeneous and complex nature of cancer. The heterogeneity and complexity of cancer presents immense obstacles and challenges to scientists and clinicians, with respect to better understanding and clinical management of cancer. Increasingly, it is recognized that the single agent approaches, which have been traditionally and broadly applied to the treatment of malignant diseases, are inadequate for treatment. Accordingly, concerted efforts have been mounted to better strategize combination and/or sequential therapies for treating a variety of tumors.
Herbal therapies may be considered a form of combination therapy. They differ from the single agent approach in that aggregate bioactive, inactive, and counter-active agents are present. The collective effect of these agents typically results in reduced toxicity, and appearance of new and novel activities. The combination of activities present in herbal therapies can be important determinants in cancer prevention/treatment since they may circumvent overlapping molecular pathways that may result in successful cancer treatment.